Use of creatine analogues and creatine kinase modulators for the prevention and treatment of glucose metabolic disorders

ABSTRACT

The present invention relates to the use of creatine compounds including cyclocreatine and creatine phosphate for treating or preventing a metabolic disorder consisting of hyperglycemia, insulin dependent diabetes mellitus, impaired glucose tolerance, hyperinsulinemia, insulin insensitivity, diabetes related diseases in a patient experiencing said disorder. The creatine compounds which can be used in the present method include (1) analogues of creatine which can act as substrates or substrate analogues for the enzyme creatine kinase; (2) compounds which can act as activators or inhibitors of creatine kinase; (3) compounds which can modulate the creatine transporter (4) N-phosphocreatine analogues bearing transferable or non-transferable moieties which mimic the N-phosphoryl group. (5) compounds which modify the association of creatine kinase with other cellular components.

RELATED APPLICATIONS

The present invention is a continuation-in-part of Ser. No. 08/540,894,filed Oct. 11, 1995, the entire disclosure of which is incorporatedherein by reference.

FIELD OF INVENTION

The present invention provides for new use for creatine compounds(compounds which modulate one or more of the structural or functionalcomponents of the creatine kinase/creatine phosphate system) astherapeutic agents. More particularly, the present invention provides amethod of treating or preventing certain metabolic disorders of humanand animal metabolism, e.g., hyperglycemia, insulin dependent diabetesmellitus, impaired glucose tolerance, insulin insensitivity,hyperinsulinemia and related diseases secondary to diabetes.

BACKGROUND OF THE INVENTION

There are several metabolic diseases of human and animal glucosemetabolism, eg., hyperglycemia, insulin dependent diabetes mellitus,impaired glucose tolerance, hyperinsulinemia, and insulin insensitivity,such as in non-insulin dependent diabetes mellitus (NIDDM).Hyperglycemia is a condition where the blood glucose level is above thenormal level in the fasting state, following ingestion of a meal orduring a glucose tolerance test. It can occur in NIDDM as well as inobesity. Hyperglycemia can occur without a diagnosis of NIDDM. Thiscondition is called impaired glucose tolerance or pre-diabetes. Impairedglucose tolerance occurs when the rate of metabolic clearance of glucosefrom the blood is less than that commonly occurring in the generalpopulation after a standard dose of glucose has been orally orparenterally administered. It can occur in NIDDM as well as obesity,pre-diabetes and gestational diabetes. Hyperinsulinemia is defined ashaving a blood insulin level that is above normal level in fasting stateor following ingestion of a meal. It can be associated with or causativeof hypertension or atherosclerosis. Insulin insensitivity, or insulinresistance occurs when the insulin-dependent glucose clearance rate isless than that commonly occurring in the general population duringdiagnostic procedures.

A number of compounds have been tried to alleviate symptoms associatedwith glucose metabolism disorders. For example, guanidine, monoguanidineand biguanidine compounds have been shown to produce hypoglycemia.Watanabe, C., J. Biol. Chem., 33:253-265 (1918); Bischoff, F. et al.,Guanidine Structures and Hypoglycemia, 81:325-349 (1929). However thesecompounds were shown to be toxic. Biguanide derivatives, e.g.,phenformin and metformin, have been used clinically as antidiabeticagents. Some members of this class continue to be used today, whileothers have been withdrawn from the market. Schafer, G., DiabetesMetabol. (Paris) 9:148-163 (1983). Gamma-guanidinobutyramide, also knownas Tyformin, and its salt derivative, Augmentin, were investigated aspotential anti-diabetic agents from the mid 1960's to mid 1970's. WhileAugmentin produced hypoglycemia, it was reported to have majorundesirable side effects such as hypertension and circulatory collapse.Malaisse, W. et al., Horm. Metab. Res., 1:258-265 (1969); ibid, 3:76-81(1971).

British patent 1,153,424 discloses the use of certain esters and amidesof guanidino-aliphatic acids in the treatment of diabetes mellitus wherehyperuremia is present. The patent does not disclose that thesecompounds have an effect on hyperglycemia or any other symptom orpathological state related to disease. Canadian patent 891509 disclosesthe use of esters and amides of guanidinoaliphatic acids were disclosedfor treating hyperuremia and hyperglycemia in diabetes mellitus.

British patents 1,195,199, and 1,195,200 disclose the use of guanidinoalkanoic acids or their amides or esters for the treatment ofhyperglycemia occurring in diabetes. A variety of British patents(1,552,179/1,195,199/1,195,200/1,552,179) describe the low potency ofthe guanidino alkanoic acid derivatives as single agents but describetheir use in combination with other modalities.

Aynsley-Green and Alberti injected rats intravenously with betaguanidino propionic acid, arginine, guanidine, 4 guanidinobutyramide and4 guanidinobutyric acid. Arginine and beta guanidino propionic acidstimulated insulin release but did not affect glucose levels. Also thetreatment of animals with large amounts of beta gunidino propionic acidfor several weeks was shown not to affect glucose levels, Moerland, T.et al., Am. J. Physiol., 257:C810-C816 (1989). Under differentconditions beta gunidino propionic acid was shown to have an effect asdescribed later. The two other compounds did stimulate insulin releasebut increased glucose levels. Aynsley-Green, A. et al., Horm. Metab.,6:115-120 (1974).

It is an object of the present invention to provide methods fortreatment of metabolic diseases that relate to glucose level regulationby administering to an afflicted individual an amount of a compound orcompounds which modulate one or more of the structural or functionalcomponents of the creatine kinase/creatine phosphate system sufficientto prevent, reduce or ameliorate the symptoms of the disease. Thesecompounds are collectively referred to as "creatine compounds." Theexperiments described herein demonstrate that the creatine kinase systemis directly related to control of blood glucose levels in animals.Creatine analogues are shown herein to be effective hypoglycemic agentsfor treatment of glucose metabolic diseases.

SUMMARY OF THE INVENTION

The present invention provides a method of treating or preventing aglucose metabolic disorder using creatine, creatine phosphate, or acompound or compounds which modulates one or more of the structural orfunctional components of the creatine kinase/creatine phosphate system.Disorders which may be treated using the present invention include, forexample, those selected from the group consisting of hyperglycemia,insulin dependent diabetes mellitus, impaired glucose tolerance,hyperinsulinemia and diabetes related complications. The method of theinvention comprises administering to a subject afflicted with orsusceptible to said disorder an amount of a creatine compound (compoundswhich modulate one or more of the structural or functional components ofthe creatine kinase/creatine phosphate system) sufficient to alleviateor prevent the symptoms of the disorder. The creatine compound may be inthe form of a pharmacologically acceptable salt or combined with anadjuvant or other pharmaceutical agent effective to treat or prevent thedisease or condition.

Prior to the present invention, the creatine kinase system had not beenimplicated in glucose metabolic disorders. The substrates for thecreatine kinase enzyme, i.e., creatine and creatine phosphate, are bothguanidino compounds. The present inventors have discovered that thecreatine kinase (CK) enzyme modifies key events involved in glucoseregulation by potentially regulating energy (ATP) involved in therelease of insulin or the uptake of glucose in tissue. It is nowpossible to modify the CK system and design compounds that can preventor ameliorate these diseases. The present invention demonstrates that atleast two creatine compounds, creatine phosphate and cyclocreatine, arehypoglycemic agents. That is, these compounds cause glucose levels todrop significantly in a subject.

As stated herein above, a variety of guanidino compounds have been shownto act as hypoglycemic agents including the compound beta guanidinopropionic acid (see, for example, PCT Publication Number WO 91/12799).The target for these compounds and their mode of action is not fullyunderstood. However, beta guanidino propionic acid was shown not toaffect glucose levels in normal animals, but had an effect on glucoselevels in a model for non-insulin dependent diabetes mellitus. Thiscompound has some structural similarity to creatine, but does not form apart of this invention. Compounds useful in the present invention arecreatine compounds which modulate the creatine kinase system.

The present invention also provides pharmaceutical compositionscontaining creatine compounds in combination with a pharmaceuticallyacceptable carrier. The present compositions may be used in combinationwith effective amounts of standard chemotherapeutic agents which act onregulating glucose levels, such as insulin or sulphonylureas, toprophylactically and/or therapeutically treat a subject with a diseaserelated to glucose levels.

Packaged drugs for treating subjects having a disease relating toglucose level regulation also are the subject of the present invention.The packaged drugs include a container holding the creatine compound, incombination with a pharmaceutically acceptable carrier, along withinstructions for administering the same for the purpose of preventing,ameliorating, arresting or eliminating a disease related to glucoselevel regulation.

By treatment is meant the amelioration of one or more symptoms of, ortotal avoidance of, the metabolic disorder as described herein. Byprevention is meant the avoidance of a currently recognized diseasestate, as described herein, in a patient evidencing some or all of theglucose metabolic disorders described above. The present compositionsmay be administered in a sustained release formulation. By sustainedrelease is meant a formulation in which the drug becomes biologicallyavailable to the patient at a measured rate over a prolonged period.Such compositions are well known in the art.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 graphically illustrates the effect of selected creatine compoundson glucose levels in rats: Panel (A): glucose levels in control(unmanipulated animals); Panel (B): glucose levels in cyclocreatinetreated animals; Panel (C): glucose levels in beta-guanidino propionicacid treated animals; and Panel (D): glucose levels in creatinephosphate treated animals.

FIG. 2 graphically illustrates the effect of the selected compounds onglucose levels in rats: Panel (A): control (unmanipulated animals);Panel (B): cyclocreatine treated; Panel (C): beta-guanidino propionicacid treated; Panel (D): creatine phosphate treated animals.

FIG. 3 graphically illustrates the average effect of selected creatinecompounds on glucose levels in rats over time: Panel (A): illustratesaverage glucose levels in cyclocreatine treated animals as compared tothe average of the control (unmanipulated animals); Panel (B):illustrates average glucose levels in beta-guanidino propionic acidtreated animals as compared to the average of the control (unmanipulatedanimals); Panel (C): illustrates average glucose levels in creatinephosphate treated animals as compared to the average of the control(unmanipulated animals).

FIG. 4 graphically illustrates the effect of cyclocreatine on glucoselevels in rabbits infused with cyclocreatine. Rabbits or HCMV infectedrabbits were infused in a continuous intravenious mode withcyclocreatine as outlined in Example 4. The cyclocreatine solution wasprepared in saline at 5 mg/ml, 10 mg/ml or 15 mg/ml and was infused todeliver amounts of drug 375-1125 mg/Kg/day. Cyclocreatine was infuseddaily for up to 7 days. Glucose levels were determined using standardprocedures (BioPure, Boston, Mass.) on several days and up to the end ofthe cyclocreatine infusion. Glucose levels were determined on severaldays and up to 7 days post cyclocreatine infusion. Panel (A) illustratesthe effect of cyclocreatine infused at 15 mg/ml on blood glucose levelsof normal rabbits. Each bar represents glucose levels in separateanimals. Panel (B) illustrates the effect of cyclocreatine infused at 10mg/ml on blood glucose levels in infected rabbits. Each bar representsglucose levels in separate animals. Panel (C) illustrates the effect ofcyclocreatine infused at 5 mg/ml on blood glucose levels of infectedrabbits. Each line represents glucose levels in separate animals.

FIG. 5 graphically illustrates the average effect of infusedcyclocreatine on glucose levels in rabbits. Animals infused with salineor cyclocreatine at different concentrations were examined for glucoselevels for up to seven days post infusion. At each concentration ofcyclocreatine glucose levels were determined in 3-4 animals and averagevalues were calculated and presented as bars.

FIG. 6 graphically illustrate the average effect of cyclocreatine overtime on glucose levels in the Male Zuker lean littermates (+/?) ascompared to Day 0. Three animals per group were treated with thecompound in the feed as described in Example 5. Solid circles () areaverages in untreated groups while open circles (∘) are averages intreated groups.

FIG. 7 graphically illustrates the average effect of cyclocreatine overtime on glucose levels in the Male Zuker diabetic fatty (ZDF-fa/fa) ratsas compared to Day 0. Three animals per group were treated with thecompound in the feed as described in Example 5. Solid squares (▪) areaverages in untreated groups while open squares (□) are averages intreated groups.

FIG. 8 graphically illustrate the average effect of creatine over timeon glucose level in the Male Zuker lean littermates (+/?) as compared toDay 0. Three animals per group were treated with the compound in thefeed as described in Example Five. Solid circles () are averages inuntreated groups while open circles (∘) are averages in treated groups.

FIG. 9 graphically illustrates the average effect of creatine over timeon glucose levels in the Male Zuker diabetic fatty (ZDF-fa/fa) rats ascompared to Day 0. Three animals per group were treated with thecompound in the feed as described in Example 5. Solid squares (▪) areaverages in untreated groups while open squares (□) are averages intreated groups.

FIG. 10 graphically illustrate the average effect of cyclocreatine overtime on insulin level in the Male Zuker lean littermates (+/?) ascompared to Day 0 Three animals per group were treated with the compoundin the feed as described in Example 5. Solid circles () are averages inuntreated groups while open circles (∘) are averages in treated groups.

FIG. 11 graphically illustrates the average effect of cyclocreatine overtime on insulin levels in the Male Zuker diabetic fatty (ZDF-fa/fa) ratsas compared to Day 0. Three animals per group were treated with thecompound in the feed as described in Example 5. Solid squares (▪) areaverages in untreated groups while open squares (□) are averages intreated groups.

FIG. 12 graphically illustrate the average effect of creatine over timeon insulin level in the Male Zuker lean littermates (+/?) as compared toDay 0. Three animals per group were treated with the compound in thefeed as described in Example 5. Solid circles () are averages inuntreated groups while open circles (∘) are averages in treated groups.

FIG. 13 graphically illustrates the average effect of creatine over timeon insulin levels in the Male Zuker diabetic fatty (ZDF-fa/fa) rats ascompared to Day 0. Three animals per group were treated with thecompound in the feed as described in Example 5. Solid squares (▪) areaverages in untreated groups while open squares (□) are averages intreated groups.

FIG. 14 graphically illustrates three individual patients' glucoselevels upon treatment with cyclocreatine at a dose of 60 mg/Kg. Patientswere treated with cyclocreatine via a 3 hour continuous infusion in aone liter volume of saline using the schedule of administration asdescribed in Example 6.

FIG. 15 graphically illustrates three individual patients' glucoselevels upon treatment with cyclocreatine at a dose of 80 mg/Kg. Patientswere treated with cyclocreatine via a 3 hour continuous infusion in aone liter volume of saline using the schedule of administration asdescribed in Example 6.

FIG. 16 graphically illustrates glucose levels in a diabetic cancerpatient upon treatment with cyclocreatine at a dose of 10 mg/Kg. Thepatient was treated with cyclocreatine via a 3 hour continuous infusionin a one liter volume of saline using the schedule of administration asdescribed in Example 6.

DETAILED DESCRIPTION OF THE INVENTION

The method of the present invention generally comprises administering toan individual afflicted with a disease or susceptible to a diseaseinvolving glucose level regulation, an amount of a compound or compoundswhich modulate one or more of the structural or functional components ofthe creatine kinase/phosphocreatine (CK/CrP) system sufficient toprevent, reduce or ameliorate symptoms of the disease. Components of theCK/CrP system which can be modulated include the enzyme creatine kinase(CK), the substrates creatine, creatine phosphate, ADP, ATP, and thetransporter of creatine. As used herein, the term "modulate" means tochange, affect or interfere with the functioning of the component in theCK/CrP enzyme system.

The CK/CrP is an energy generating system operative predominantly in thebrain, muscle, heart, retina, and the pancreas. Wallimann et. al. ,Biochem. J., 281, 21-401 (1992). The components of the system includethe enzyme creatine kinase (CK), the substrates creatine (Cr), creatinephosphate (CrP), ATP, ADP, and the creatine trasporter. The enzymereversibly catalyzes the transfer of a phosphoryl group from CrP to ADPto generate ATP. It is found to be localized at sites where rapid rateof ATP replenishment is needed. Some of the functions associated withthis system include efficient regeneration of energy in the form of ATPin cells with fluctuating and high energy demand, energy transport todifferent parts of the cell, phosphoryl transfer activity, ion transportregulation, and involvement in signal transduction pathways.

The substrate creatine is a compound which is naturally occurring and isfound in mammalian brain, skeletal muscle, retina and the heart. It'sphosphorylated form CrP is also found in the same organs and is theproduct of the CK reaction. Both compounds can be easily synthesized andare believed to be non-toxic to man. A series of creatine analogues havealso been synthesized and used as probes to study the active site of theenzyme. Kaddurah-Daouk et al. (WO 92/08456 published May 29, 1992 and WO90/09192, published Aug. 23, 1990; U.S. Pat. Nos. 5,321,030; and5,324,731, the entire disclosures of which are hereby incorporatedherein by reference) described methods for inhibiting growth,transformation, or metastasis of mammalian cells using relatedcompounds. Examples of such compounds include cyclocreatine,homocyclocreatine and beta guanidino propionic acid. These sameinventors have also demonstrated the efficacy of such compounds forcombating viral infections (U.S. Pat. No. 5,321,030). Elgebaly in U.S.Pat. No. 5,091,404 discloses the use of cyclocreatine for restoringfunctionality in muscle tissue. Cohn in PCT publication No. WO94/16687describes a method for inhibiting the growth of several tumors usingcreatine and related compounds. No prior work has established a directlink between the creatine kinase system and diseases related to glucoselevel regulation such as hyperglycemia, insulin dependent or independentdiabetes and related diseases secondary to diabetes.

Compounds which are particularly effective for use in the presentinvention include cyclocreatine, creatine phosphate and analoguesthereof which are described below. The term "creatine compound" will beused herein to include Cr, CrP, cyclocreatine, compounds which arestructurally similar to Cr, CrP, and cyclocreatine, and analogues of Cr,CrP, and cyclocreatine. The term "creatine compound" also includescompounds which "mimic" the activity of cyclocreatine and creatinephosphate or creatine analogues i.e., compounds which modulate thecreatine kinase system. The term "mimics" is intended to includecompounds which may not be structurally similar to creatine but mimicthe therapeutic activity of the creatine analogues cyclocreatine andcreatine phosphate or structurally similar compounds. The term creatinecompounds will also include inhibitors of creatine kinase, ie. compoundswhich inhibit the activity of the enzyme creatine kinase, molecules thatinhibit the creatine transporter or molecules that inhibit the bindingof the enzyme to other structural proteins or enzymes or lipids. Theterm "modulators" of the creatine kinase system" are compounds whichmodulate the activity of the enzyme, or the activity of the transporterof creatine, or the ability of the enzyme to associate with othercellular components. These could be substrates for the enzyme and theywould have the ability to build in their phosphorylated stateintracellularly. These types of molecules are also included in our termcreatine compounds. The term creatine "analogue" is intended to includecompounds which are structurally similar to creatine such ascyclocreatine and creatine phosphate, compounds which are art-recognizedas being analogues of creatine, and/or compounds which share the samefunction as cyclocreatine and creatine phosphate.

Creatine (also known as N-(aminoiminomethyl)-N-methyl glycine;methylglycosamine or N-methyl-guanidino acetic acid) is a well-knownsubstance. See, The Merck Index, Eleventh Edition No. 2570 (1989).Creatine is phosphorylated chemically or enzymatically to creatinekinase to generate creatine phosphate, which is also well known (see,The Merck Index, No. 7315). Both creatine and creatine phosphate(phosphocreatine) can be extracted from animals or tissue or synthesizedchemically. Both are commercially available.

Cyclocreatine is an essentially planar cyclic analogue of creatine.Although cyclocreatine is structurally similar to creatine, the twocompounds are distinguishable both kinetically and thermodynamically.Cyclocreatine is phosphorylated efficiently by the enzyme creatinekinase in the forward reaction, both in vitro and in vivo. Rowley, G.L., J. AM. Chem. Soc., 93:5542-5551 (1971); McLaughlin, A. C. et. al.,J. Biol. Chem., 247, 4382-4388 (1972). It represents a class ofsubstrate analogues of creatine kinase and which are believed to beactive.

Examples of creatine analogues known or believed to modify the creatinekinase/creatine phosphate system are listed in Tables 1 and 2.

                                      TABLE 1                                     __________________________________________________________________________    CREATINE ANALOGS                                                              __________________________________________________________________________     ##STR1##                                                                                     ##STR2##                                                       ##STR3##                                                                                     ##STR4##                                                       ##STR5##                                                                                     ##STR6##                                                       ##STR7##                                                                                     ##STR8##                                                       ##STR9##                                                                                     ##STR10##                                                                                    ##STR11##                                       ##STR12##                                                                                    ##STR13##                                                                                    ##STR14##                                       ##STR15##                                                                                    ##STR16##                                                      ##STR17##                                                                    __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    CREATINE PHOSPHATE ANALOGS                                                    __________________________________________________________________________     ##STR18##                                                                                        ##STR19##                                                  ##STR20##                                                                                        ##STR21##                                                  ##STR22##                                                                                        ##STR23##                                                  ##STR24##                                                                                        ##STR25##                                                  ##STR26##                                                                                        ##STR27##                                                  ##STR28##                                                                                        ##STR29##                                                  ##STR30##                                                                                        ##STR31##                                                  ##STR32##                                                                    __________________________________________________________________________

Most of these compounds have been previously synthesized for otherpurposes. Rowley et. al., J. Am. Chem. Soc., 93:5542-5551 (1971);Mclaughlin et. al., J. Biol. Chem., 247:4382-4388 (1972); Nguyen, A. C.K., "Synthesis and enzyme studies using creatine analogues", Thesis,Dept of Pharmaceutical Chemistry, Univ. Calif., San Francisco, (1983);Lowe et al., J. Biol. Chem., 225:3944-3951 (1980); Roberts et. al., J.Biol. Chem, 260:13502-13508 (1995); Roberts et. al., Arch. biochem.Biophy., 220:563-571 (1983), and Griffiths et. al., J. Biol. Chem.,251:2049-2054 (1976). The contents of all of the aforementionedreferences are expressly incorporated herein by reference. Further tothe aforementioned references, Kaddurah-Daouk et. al., (WO 92108456; WO90/09192; U.S. Pat. Nos. 5,324,731; 5,321,030) also provide citationsfor the synthesis of a plurality of creatine analogues. The contents ofall the aforementioned references and patents are hereby incorporatedherein by reference.

It is possible to modify the substances described below to produceanalogues which have enhanced characteristics, such as greaterspecificity for the enzyme, enhanced solubility or stability, enhancedcellular uptake, or better binding activity. Salts of products may beexchanged to other salts using standard protocols.

Bisubstrate analogues of creatine kinase and non hydrolyizable substrateanalogues of creatine phosphate (non transferable moieties which mimicthe N phosphoryl group of creatine phosphate) can be designed readilyand would be examples of creatine kinase modulators. Creatine phosphatecompounds can be synthesized chemically or enzymatically. The chemicalsynthesis is well known. Annesley, T. M., Walker, J. B., Biochem.Biophys. Res. Commun., 74:185-190 (1977); Cramer, F., Scheiffele, E.,Vollmar, A., Chem. Ber., 95:1670-1682 (1962).

Creatine compounds which are particularly useful in this inventioninclude those encompassed by the following general formula: ##STR33##and pharmaceutically acceptable salts thereof, wherein: a) Y is selectedfrom the group consisting of: --CO₂ H--NH)H, --NO₂, --SO₃ H,--C(═O)NHSO₂ J and --P(═O)(OH)(OJ), wherein J is selected from the groupconsisting of: hydrogen, C₁ -C₆ straight chain alkyl, C₃ -C₆ branchedalkyl, C₂ -C₆ alkenyl, C₃ -C₆ branched alkenyl, and aryl;

b) A is selected from the group consisting of: C, CH, C₁ -C₅ alkyl, C₂-C₅ alkenyl, C₂ -C₅ alkynyl, and C₁ -C₅ alkoyl chain, each having 0-2substituents which are selected independently from the group consistingof:

1) K, where K is selected from the group consisting of: C₁ -C₆ straightalkyl, C₂ -C₆ straight alkenyl, C₁ -C₆ straight alkoyl, C₃ -C₆ branchedalkyl, C₃ -C₆ branched alkenyl, and C₄ -C₆ branched alkoyl, K having 0-2substituents independently selected from the group consisting of: rromo,chloro, epoxy and acetoxy;

2) an aryl group selected from the group consisting of: a 1-2 ringcarbocycle and a 1-2 ring heterocycle, wherein the aryl group contains0-2 substituents independently selected from the group consisting of:--CH₂ L and --COCH₂ L where L is independently selected from the groupconsisting of: bromo, chloro, epoxy and acetoxy; and

3) --NH--M, wherein M is selected from the group consisting of:hydrogen, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₁ -C₄ alkoyl, C₃ -C₄ branchedalkyl, C₃ -C₄ branched alkenyl, and C₄ branched alkoyl;

c) X is selected from the group consisting of NR₁, CHR₁, CR₁, O and S,wherein R₁ is selected from the group consisting of:

1) hydrogen;

2) K where K is selected from the group consisting of: C₁ -C₆ straightalkyl, C₂ -C₆ straight alkenyl, C₁ -C₆ straight alkoyl, C₃ -C₆ branchedalkyl, C₃ -C₆ branched alkenyl, and C₄ -C₆ branched alkoyl, K having 0-2substituents independently selected from the group consisting of: bromo,chloro, epoxy and acetoxy;

3) an aryl group selected from the group consisting of a 1-2 ringcarbocycle and a 1-2 ring heterocycle, wherein the aryl group contains0-2 substituents independently selected from the group consisting of:--CH₂ L and --COCH₂ L where L is independently selected from the groupconsisting of: bromo, chloro, epoxy and acetoxy;

4) a C₅ -C₉ a-amino-w-methyl-w-adenosylcarboxylic acid attached via thew-methyl carbon;

5) 2 C₅ -C₉ a-amino-w-aza-w-methyl-w-adenosylcarboxylic acid attachedvia the w-methyl carbon; and

6) a C₅ -C₉ a-amino-w-thia-w-methyl-w-adenosylcarboxylic acid attachedvia the w-methyl carbon;

d) Z₁ and Z₂ are chosen independently from the group consisting of: ═O,--NHR₂, --CH₂ R₂, --NR₂ OH; wherein Z₁ and Z₂ may not both be ═O andwherein R₂ is selected from the group consisting of:

1) hydrogen;

2) K, where K is selected from the group consisting of: C₁ -C₆ straightalkyl; C₂ -C₆ straight alkenyl, C₁ -C₆ straight alkoyl, C₃ -C₆ branchedalkyl, C₃ -C₆ branched alkenyl, and C₄ -C₆ branched alkoyl, K having 0-2substituents independently selected from the group consisting of: bromo,chloro, epoxy and acetoxy;

3) an aryl group selected from the group consisting of a 1-2 ringcarbocycle and a 1-2 ring heterocycle, wherein the aryl group contains0-2 substituents independently selected from the group consisting of:--CH₂ L and --COCH₂ L where L is independently selected from the groupconsisting of: bromo, chloro, epoxy and acetoxy;

4) 2 C₄ -C₈ a-amino-carboxylic acid attached via the w-carbon;

5) B, wherein B is selected from the group consisting of: --CO₂ H--NHOH,--SO₃ H, --NO₂, OP(═O)(OH)(OJ) and --P(═O)(OH)(OJ), wherein J isselected from the group consisting of: hydrogen, C₁ -C₆ straight alkyl,C₃ -C₆ branched alkyl, C₂ -C₆ alkenyl, C₃ -C₆ branched alkenyl, andaryl, wherein B is optionally connected to the nitrogen via a linkerselected from the group consisting of: C₁ -C₂ alkyl, C₂ alkenyl, and C₁-C₂ alkoyl;

6) --D--E, wherein D is selected from the group consisting of: C₁ -C₃straight alkyl, C₃ branched alkyl, C₂ -C₃ straight alkenyl, C₃ branchedalkenyl, C₁ -C₃ straight alkoyl, aryl and aroyl; and E is selected fromthe group consisting of: --(PO₃)_(n) NMP, where n is 0-2 and NMP isribonucleotide monophosphate connected via the 5'-phosphate,3'-phosphate or the aromatic ring of the base; --[P(═O)(OCH₃)(O)]_(m)--Q, where m is 0-3 and Q is a ribonucleoside connected via the riboseor the aromatic ring of the base; --[P(═O)(OH)(CH₂)]_(m) --Q, where m is0-3 and Q is a ribonucleoside connected via the ribose or the aromaticring of the base; and an aryl group containing 0-3 substituents chosenindependently from the group consisting of: Cl, Br, epoxy, acetoxy,--OG, --C(═O)G, and --CO₂ G, where G is independently selected from thegroup consisting of: C₁ -C₆ straight alkyl, C₂ -C₆ straight alkenyl, C₁-C₆ straight alkoyl, C₃ -C₆ branched alkyl, C₃ -C₆ branched alkenyl, C₄-C₆ branched alkoyl, wherein E may be attached to any point to D, and ifD is alkyl or alkenyl, D may be connected at either or both ends by anamide linkage; and

7) --E, wherein E is selected from the group consisting of --(PO₃)_(n)NMP, where n is 0-2 and NMP is a ribonucleotide monophosphate connectedvia the 5'-phosphate, 3'-phosphate or the aromatic ring of the base;--[P(═O)(OCH₃)(O)]_(m) --Q, where m is 0-3 and Q is a ribonucleosideconnected via the ribose or the aromatic ring of the base;--[P(═O)(OH)(CH₂)]_(m) --Q, where m is 0-3 and Q is a ribonucleosideconnected via the ribose or the aromatic ring of the base; and an arylgroup containing 0-3 substituents chose independently from the groupconsisting of: Cl, Br, epoxy, acetoxy, --OG, --C(═O)G, and --CO₂ G,where G is independently selected from the group consisting of: C₁ -C₆straight alkyl, C₂ -C₆ straight alkenyl, C₁ -C₆ straight alkoyl, C₃ -C₆branched alkyl, C₃ -C₆ branched alkenyl, C₄ -C₆ branched alkoyl; and ifE is aryl, E may be connected by an amide linkage;

e) if R₁ and at least one R₂ group are present, R₁ may be connected by asingle or double bond to an R₂ group to form a cycle of 5 to 7 members;

f) if two R₂ groups are present, they may be connected by a single or adouble bond to form a cycle of 4 to 7 members; and

g) if R₁ is present and Z₁ or Z₂ is selected from the group consistingof --NHR₂, --CH₂ R₂ and --NR₂ OH, then R₁ may be connected by a singleor double bond to the carbon or nitrogen of either Z₁ or Z₂ to form acycle of 4 to 7 members. Currently preferred compounds includecyclocreatine, creatine phosphate and those included in Tables 1 and 2hereinabove.

The modes of administration for these compounds include, but are notlimited to, oral, transdermal, or parenteral (e.g., subcutaneous,intramuscular, intravenous, bolus or continuous infusion). The actualamount of drug needed will depend on factors such as the size, age andseverity of disease in the afflicted individual. Creatine has beenadministered to athletes in the range of 2-8 gms/day to improve musclefunction. Creatine phosphate was administered to patients withcongestive heart failure also in the range of several gm/day, and wasvery well tolerated. In experimental animal models of cancer or viralinfections, where creatine compounds have been shown to be active,amounts of 1 gm/kg/day were administered intravenously orintraperitoneially. For this invention the creatine compound will beadministered at dosages and for periods of time effective to reduce,ameliorate or eliminate the symptoms of the disease. Dose regimens maybe adjusted for purposes of improving the therapeutic or prophylacticresponse of the compound. For example, several divided doses may beadministered daily, one dose, or cyclic administration of the compoundsto achieve the desired therapeutic result. Agents that improve thesolubility of these compounds could also be added.

The creatine compounds can be formulated with one or more adjuvantsand/or pharmaceutically acceptable carriers according to the selectedroute of administration. The addition of gelatin, flavoring agents, orcoating material can be used for oral applications. For solutions oremulsions in general, carriers may include aqueous or alcoholic/ aqueoussolutions, emulsions or suspensions, including saline and bufferedmedia. Parenteral vehicles can include sodium chloride, potassiumchloride among others. In addition, intravenous vehicles can includefluid and nutrient replenishers, electrolyte replenishers among others.

Preservatives and other additives can also be present. For example,antimicrobial, antioxidant, chelating agents, and inert gases can beadded (see, generally, Remington's Pharmaceutical Sciences, 16thEdition, Mack, (1980)).

The present invention is demonstrated more fully by the followingexamples, which are not intended to be limiting in any way:

EXAMPLE 1 Effect of Creatine Compounds on Glucose Levels in Rats BearingTumors

Two creatine compounds, creatine phosphate and cyclocreatine, wereinjected intravenously into tumor bearing rats, and the level of glucosein the rats was monitored. Beta guanidino propionic acid, also wasadministered. This compound was previously shown to have no effect onglucose levels in normal animals but was shown to modify glucose levelsin NIDDM models. There was no specific reason for using tumor bearingrats, except convenience because the antitumor activity of thesecompounds also was being studied. The presence of the tumors should nothave any effect on the ability of these compounds to regulate glucoselevels.

The rats carrying the tumors were described by us previously (see,Teisher et al., Cancer Chemother. Pharmacol, 35:411-416, 1995). Theschedule and dose selected in these experiments was based on priorexperience working with this class of compounds as anticancer orantiviral chemotherapeutic agents. The rat mammary adenocarcinoma 13762was implanted in the female Fisher 344 rats on day zero. The creatinecompounds were administered intravenously on days 4-8 and days 14-18.The amounts used were 1 gm/kg of cyclocreatine, 0.93 gm/kg for betaguanidino propionic acid, and 2.32 gm/kg for creatine phosphate. We weretargeting a 1 gm/kg molar equivalent of creatine to achieve mM levelsknown typically to be needed with creatine analogues to modulate thecreatine kinase system intracellularly. Plasma glucose levels weremeasured at around 11 a.m., by taking a drop of blood from the animalsand testing glucose levels using a commercial kit (CHEMSTRIP bG,Boehringer Mannheim). For animals that were treated with drugs, thetreatment was around 9 a.m., and bleeding was also at around 11 a.m.

FIG. 1 shows the results of our first experiment graphically. Panel (A):glucose levels in control (unmanipulated animals); Panel (B): glucoselevels in cyclocreatine treated animals; Panel (C): glucose levels inbeta-guanidino propionic acid treated animals; and Panel (D): glucoselevels in creatine phosphate treated animals. The controls showed anaverage glucose level in rats of 62 mg/dl. The treatment withcyclocreatine showed two drops in glucose levels at the time of drugadministration, i.e., between days 4-8 and days 14-18. The drop inglucose level at the second cycle of drug administration was moredramatic than the first cycle, consistent with what is known about thecontinuous build up of these compounds in organs high in creatine kinaseactivity. Minimal changes in glucose levels were seen with betaguanidino propionic acid treatment consistent with previous publisheddata. The compound creatine phosphate induced similar pattern of dropsin glucose levels as that seen with cyclocreatine, althoughcyclocreatine seemed to be more potent.

EXAMPLE 2 Effect of Creatine Compounds on Glucose Levels in Rats BearingTumors

The same experiment described above was repeated. FIG. 2 shows theeffect of the selected compounds on glucose levels. Panel (A): control(unmanipulated animals); Panel (B): cyclocreatine treated; Panel (C):beta-guanidino propionic acid treated; Panel (D): creatine phosphatetreated animals. The same pattern seen in Example 1 is also seen here.Cyclocreatine induced a drop in the level of glucose after eachadministration. The drop in the second cycle was more dramatic than thefirst. Beta-guanidino propionic acid had minimal effect, and creatinephosphate seemed to mirror the effect of cyclocreatine.

EXAMPLE 3 Effect of Creatine Compounds on Glucose Levels in Rats BearingTumors

To examine more closely what occurred in the above two experiments, theaverage readings of glucose levels from experiments one and two weretaken in the following time intervals post drug treatment: Days 2-3,Days 4-8, Days 8-12, Days 14-18, Day 15 and Days 19-22. Day 15demonstrates the largest effect on glucose levels by this class ofcompounds. FIG. 3 outlines these results. Cyclocreatine, Panel (A),shows a drop in glucose level that could be as high as 50% on day 15.Beta-guanidino propionic acid, Panel (B), shows minimal effects <15%,and creatine phosphate, Panel (C), seems to drop glucose levels by 35%on day 15.

The experiments described above demonstrate that creatine analogueswhich modulate the creatine kinase system, and that are represented bycyclocreatine and creatine phosphate, can regulate glucose levels. Thecreatine kinase enzyme system creatine kinase emerges as a novel targetfor drug design for diseases related to the control of glucose levels.

EXAMPLE 4 Effect of Cyclocreatine on Glucose Levels in Rabbits

The creatine compound cyclocreatine, was given as a continuousintravenous infusion (IV) to normal rabbits or rabbits infected with thehuman cytomegalovirus (HCMV) in their eyes (Rabbit Chorioretinal model).Glucose levels were recorded over a period of seven days. This compoundwas tested in infected as well as in normal animals due to the fact thatthese compounds were also being evaluated as anti viral agents, abiological activity that were reported in the U.S. Pat. No. 5,321,030.As will become clear in the data presented here the eye infection had noeffect on the levels of glucose recorded. The schedule and dose selectedin these experiments was based on prior experience working with thisclass of compounds as antiviral agents.

A total of 11 NZW rabbits weighing 1.75-2.0 Kg were used in theexperiments. All animals were infused with various doses ofcyclocreatine over a period of 1-7 days in a continuous infusion mode.Continuous infusions were achieved by surgical implantation of anindwelling catheter implant into the jugular vein by standard surgicalprocedures. The catheter was threaded through a steel sleeve and swivelapparatus attached to the back of the animal's neck which was anchoredto a specially fitted vest. A Harvard Apparatus 2200 unifusion pumpmaintained drug delivery at a constant rate through out the experiment.This arrangement allowed the animal unimpaired movement within its cage.Animals received a bolus injection of antibiotics immediately aftersurgery and daily if needed. After animals recovered from theanesthesia, some animals were inoculated by intravitreal injection ofAD169 HCMV (10⁵ pfu). The remaining animals were left uninfected. Bothinfected and uninfected animals received a continuous infusion ofcyclocreatine or saline for up to seven days. Concentrations ofcyclocreatine were 5, 10, or 15 mg cyclocreatine/mil saline and infusionrates and volumes were adjusted to achieve the desired dose of 375-1125mg/Kg/day. These concentrations were based on amounts required toachieve other biological activities such as antiviral or anticancer.Volumes did not exceed the animal's normal daily intake of fluids (basedupon the assumed water consumption of roughly 100-150 ml/Kg/day; Harknesand Wagner, 1985). The rest of the animals received a similar volume ofsterile saline. On days 0, 1, 3, 5 and 7 blood was withdrawn from theear veins and glucose levels were determined.

Blood glucose levels in these rabbits that were allowed to freely feedranged from 169-201 mg/dl. The average level determined in this assaywas around 177 mg/dl which is slightly higher than that reported forrabbits in the fasting state. Table 3 summarizes levels of glucose intreated and untreated animals over a period of up to seven days.

                                      TABLE 3                                     __________________________________________________________________________    Glucose Levels In Cyclocreatine Infused Rabbits                               Drug Conc. (mg/ml)                                                                     0  5  5  5  ave 5                                                                            10 10 10 10 ave 10                                                                            15 15 15 ave 15                       __________________________________________________________________________    Infected (HCMV)                                                                        yes                                                                              yes                                                                              yes                                                                              yes   yes                                                                              yes                                                                              yes                                                                              yes    no no no                              0        177                                                                              177                                                                              177                                                                              177                                                                              177                                                                              169                                                                              194                                                                              201                                                                              184                                                                              187 177                                                                              177                                                                              177                                                                              177                          1        152                                                                              104                                                                              94 93 97 118                                                                              89 76 81 91                                        3        179                                                                              70 49 47 55 103                                                                              98 74 85 90  48 59    54                           4                       59 69 87 65 70                                        5           29 41 33 34 45 62 55 53 54     7  22 15                           6                                             22 22                           (10 ml/rabbit 20%                             73 73                           Dextrose)* 7                                                                  __________________________________________________________________________

FIG. 4 illustrates graphically the effect of cyclocreatine glucoselevels on each treated animal, and FIG. 5 illustrates the averageeffects on glucose levels seen in these animals. As shown in Table 3 andFIGS. (4 and 5), animals that were uninfected and treated withcyclocreatine at a dose of 15 mg/ml (1125 mg/Kg/day) experienced asignificant drop in their glucose levels. By day three glucose levelswere in the range of 48-59 mg/dl; by day five they were 7-22 mg/dl andthe animals became very lethargic. The administration of 10 mls of a 20%solution of dextrose on day 7 brought back the level of glucose to 70mg/dl and the animals seemed to quickly recover and resumed normalactivity and eating. These data clearly suggest that cyclocreatine is apotent regulator of blood glucose levels and that the creatine kinasesystem must be involved in glucose metabolism and homeostasis. Lowerdoses of cyclocreatine were tested in infected animals. At doses of 10mg/ml (750 mg/Kg/day) and 5 mg/ml (375 mg/Kg/day) the same observationwas noted, ie a significant drop in blood glucose levels (Table 3 andFIGS. 4 and 5). As early as day one drops in glucose levels were notedwith averages going down to the 90mg/dl range and by day five the rangewas in the 30-50 mg/dl. Some glucose levels in the animals treated with5 mg/ml cyclocreatine seem to have a lower level than those treated with10 mg/ml. We believe this is experimental variation due to thecomplexity of the setting requiring experiments to be done on separatedays. What is very clear from all of these experiments is thatcyclocreatine has definite and very reproducible effects on loweringblood glucose levels in rabbits. Infections in the eye do not seem tohave an impact on blood glucose levels, as animals infected and infusedwith saline experienced no drop in blood glucose Table 3. These salineinfused animals also illustrate that saline alone has no effect on bloodglucose levels.

EXAMPLE 5 The Effect of Cyclocreatine on Glucose Levels and Insulin in aDiabetic Animal

This preliminary study was initiated to gain insight into the potentialregulation of glucose levels by creatine compounds in ZDF rats, a widelystudied rodent model of NIDDM (Peterson, Lessons from Animal Diabetes,1994, Pages 225-230). Male Zuker diabetic fatty (ZDF-fa/fa) rats andtheir lean Zuker littermates (ZDF +/?) were from Genetic Models, Inc.,Indianapolis, Ind. This model shows diabetic characteristics whichappear to mimic human adult onset diabetes. Hyperglycemia is initiallymanifested at about 7 weeks of age and all obese rats are fully diabeticby 12 weeks of age (fed blood glucose of greater than 500 mg %). Thislevel of hyperglycemia increases slightly for several weeks thereafter.Between 7 and 10 weeks, blood insulin levels are high but thesesubsequently drop as the pancreatic beta cells cease to respond to theglucose stimulus. The lean (ZDF/Gmi) rats are the control counterpartsof the diabetic animals. These rats have the same genetics as the obeseanimals except for the obesity trait. No phenotypic differences havebeen observed between these rats and other typical lean control rats.Hence these animals represent an excellent control for the obesediabetic animals.

Male Zuker diabetic fatty (ZDF-fa/fa) rats and Zuker lean littermates(ZDF +/?) were 12 weeks old when dosing with creatine compounds wasinitiated. The ZDF-fa/fa rats were completely diabetic. The littermateswere the same age. The average weight and food intake was 360 gm and 28gm/day for the ZDF fatty rats and 300 gm and 20 gm/day for their leanlittermates. Animals were housed and dosed 3 per cage. Untreated animalswere fed Purina modified lab chow 5001. The creatine compoundscyclocreatine and creatine were given in the feed as 1% of the diet. ThePurina rodent chow (5001) was formulated to contain 1% creatine or 1%cyclocreatine. Formulations were prepared by Purina Test Diets,Richmond, Ind. Both treated and untreated animals feed ad libitum andhad free access to water. Animals were bled regularly throughout theexperiment and glucose and insulin levels were determined using standardprocedures (Linco RI-13K). FIGS. 6 and 7 illustrate the average (n=3)effect of cyclocreatine over time on glucose levels in the lean andfatty diabetic animals respectively. FIGS. 8 and 9 illustrate theaverage (n=3) effect of creatine over time on glucose levels in the leanand fatty diabetic animals respectively. FIGS. 10 and 11 illustrate theaverage (n=3) effect of cyclocreatine over time on insulin levels in thelean and fatty diabetic animals respectively. FIGS. 12 and 13 illustratethe average (n=3) effect of creatine over time on insulin levels in thelean and fatty diabetic animals respectively. Cyclocreatine as 1% of thediet dropped the level of glucose in the lean rats by about 15% (FIG.6). In the obese diabetic animals, glucose levels in the untreatedgroups continued to rise by up to 40% (FIG. 7) while those oncyclocreatine experienced a drop of close to 20%. This illustrates thatcyclocreatine is capable of regulating glucose levels in the diabeticstate. Creatine had minimal effect on glucose levels in both the leanand the diabetic animals (FIGS. 8, 9).

FIG. 10 illustrates the average effect of cyclocreatine on insulinlevels in lean animals which seem to drop significantly over 50%. FIG.11 illustrates the average effect on insulin levels in obese fattyanimals which seem to be minimally affected. FIG. 12 illustrates theaverage effect of creatine on insulin levels in lean animals which seemsto show a modest up regulation, and FIG. 13 illustrates the averageeffect of creatine on insulin levels in obese fatty animals which alsoseem to be slightly elevated.

EXAMPLE 6 The Effect of Cyclocreatine on Glucose Levels in CancerPatients

Cyclocreatine was tested in humans in a phase I/II open label doseescalation study. The patient population was terminal cancer patientsbecause cyclocreatine has demonstrated antitumor activity when used as asingle agent or in combination therapy. Cyclocreatine was administeredat doses that ranged from 10 mg/Kg to 100 mg/Kg. The schedule ofadministration of cyclocreatine is described in Table 4.

                                      TABLE 4                                     __________________________________________________________________________    Table II: Clinical Schedule of Cyclocreatine Dose Administration in           Cancer Patients                                                               __________________________________________________________________________    WEEK                                                                          DAY  1 2 3 4 5 6 7 8 9 10                                                                              11                                                                              12                                                                              13                                                                              14                                                                              15                                                                              16                                                                              17                                                                              18                                                                              19                                                                              20                                                                              21                                                                              22                                                                              23                                                                              24                         __________________________________________________________________________    DOSING                                                                             x             x x           x x x         x x x                          __________________________________________________________________________    WEEK                                                                          DAY  25                                                                              26                                                                              27                                                                              28                                                                              29                                                                              30                                                                              31                                                                              32                                                                              33                                                                              34                                                                              35                                                                              36                                                                              37                                                                              38                                                                              39                                                                              40                                                                              41                                                                              42                                                                              43                                                                              44                                                                              45                                                                              46                                                                              47                                                                              48                         __________________________________________________________________________    DOSING                                                                             x       x x x x x                                                        __________________________________________________________________________    WEEK                                                                          DAY  49 50                                                                              51                                                                              52 53                                                                              54                                                                              55                                                                              56 57                                                                              58                                                                              59                                                                              60                                                                              61 62                                                                              63                                                                              64                                                                              65                                                                              66                                                                              67                                                                              68                                                                              69                                                                              70                         __________________________________________________________________________    DOSING  x x x  x x                                                            __________________________________________________________________________

Cohorts of 3 patients were administered drug at each dose level, via a 3hour continuous infusion in one liter volume of saline. The first weekpatients received cyclocreatine once, the second week patients receivedcyclocreatine twice, the third week three times, the fourth week fourtimes, the fifth week five times. On weeks six and seven, no drug wasadministered to allow the drug to wash out. On week eight, cyclocreatinewas given five times. The study included a total of 23 patients (18male, 5 female) with a median age of 71 years (range 54-85). Thepatients had different types of malignancies. Eligibility requirementsincluded patients who have failed standard therapy or for whom notherapy was available, normal organ function, have recovered from priortherapies, probability of survival of greater than three months. Reasonsfor exclusion included: major surgery, life threatening concurrentillness and CNS metastasis. Blood samples were collected at baseline and1 day before and after the last weekly drug administration on days 1, 7,9, 14, 17, 21, 25, 28, 33, 40, 47, 49, 54, 61, and 69. Glucose levelswere determined for these collected blood samples. Significanthypoglycemia was noted at the highest tested drug concentrations (2 outof 3 patients treated at the 80 mg/Kg level and 2 out of 7 at the 100mg/Kg dose). These patients became lethargic and hypoglycemic andrequired immediate intervention to revert glucose levels. At the lowertested drug concentrations there seemed to be a trend towards a drop inglucose levels shortly after drug administration. Not all patientsexperienced a significant drop in glucose although the trend was there.FIGS. 14 and 15 illustrate graphically individual patients' glucoselevels upon treatment with 60 mg/Kg or 80 mg/Kg cyclocreatine. Patient(A) at the 80 mg/Kg dose was diabetic and had many serious complicationsdue to his disease. Insulin was withdrawn in the middle of the study dueto these complications and that resulted in marked increase in hisglucose level. His glucose did not seem to respond well tocyclocreatine. Tables 5-10 give the raw data for glucose levels inindividual patients. It should be noted that an insufficient number ofreadings was made shortly after drug administration. It is interestingto note that several patients who were diabetic or had higher glucoselevels than normal did respond to cyclocreatine, onen example beingillustrated in FIG. 16.

                  TABLE 5                                                         ______________________________________                                        Glucose (mg/dl) (Normal 70-150)                                                         Patient                                                                       11   12          13                                                           Dose (mg/Kg)    Ave                                                 Study Day   60     60          60   60                                        ______________________________________                                        0           118    83          147  116                                       1           78     80          100  39                                        7           141    72          48   37                                        9           89     92               91                                        14          108    105         93   102                                       17          92     73          92   36                                        21          90     138         82   103                                       26          90     68          75   78                                        28                 74          56   65                                        33                 113         85   99                                        40                 83          67   75                                        47                 95          142  119                                       49                 98          106  102                                       54                             72   72                                        61                 106         64   85                                        69                 112         141  127                                       ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        Glucose (mg/dl) (Normal 70-150)                                                         Patient                                                                       14   15          16     Ave                                                   Dose (mg/Kg)                                                        Study Day   80     80          80   80                                        ______________________________________                                        0           172    100         182  151                                       1           33     85          102  73                                        7           243    93          102  146                                       9           378    65          68   170                                       14          198    88          94   127                                       17          291    63          47   134                                       21          271    72          30   172                                       25          352    62               207                                       28          364    89               227                                       33          345    67               206                                       40          175    106              141                                       47                 77               77                                        49          280    89               185                                       54          416    87               252                                       61                 81               81                                        69                 81               81                                        ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        Glucose (mg/dl) (Normal 70-150)                                               Patient                                                                       17         18     19     20    21   22   23   Ave                             Dose(mg/Kg)                                                                   Study Day                                                                             100    100    100  100   100  100  100  100                           ______________________________________                                        0       121    122    115  104   158  137  168  132                           1       122    98     101  104   178  170  216  141                           7       127    104    87   160   99   108  228  130                           9       145    84     92   77    246  91   173  130                           14      71     126         90    100  87        95                            17      150    97          151        84   184  133                           21      104    85     50   76         77   163  101                           25      102    80          111        77   257  125                           28      125    71          137        109  325  153                           33      136    119         165        143  288  170                           40      162    109         141        107       130                           47      108    114         101        121       111                           49      80     95          99         119       98                            54      114    49          91         71        81                            61      122    80                     109       104                           69      86     84                     107       92                            ______________________________________                                    

                  TABLE 8                                                         ______________________________________                                        Glucose (mg/dl) (Normal 70-150)                                                      Patient                                                                       1    2      3       2,1  2,2   2,3  Ave                                       Dose (mg/Kg)                                                           Study Day                                                                              10     10     10    10   10    10   10                               ______________________________________                                        0        180    122    121   99   108   109  123                              1                      125   78   84    138  119                              7        229    119    77    85   83    144  123                              9        170    115    116   83   118   109  119                              14              126          81   126   105  110                              17       67            72    108        84   83                               21       82     223    108   101  89    225  138                              25       82     141    96    100  93         102                              28              59     70    103  90    97   84                               33       84     97     94    76   110   54   86                               40       136    89     98    80   109   214  121                              47       58     117    95    86         128  97                               49       147                 93   191   223  164                              54       160    103    85    107        56   102                              61       125    128          100        171  131                              69       104    124    104   90         335  151                              ______________________________________                                    

                  TABLE 9                                                         ______________________________________                                        Glucose (mg/dl) (Normal 70-150)                                               Patient                                                                       4          5      6      7     2,4  2,5  2,6  Ave                             Dose (mg/Kg)                                                                  Study Day                                                                             20     20     20   20    20   20   20   20                            ______________________________________                                        0       84     117    85   240   151  77   84   120                           1       77     91     83   201   232  96   121  129                           7       85     114    141  120   80   96   137  110                           9       79     84          161        104  131  112                           14      93                 207   181  99   138  144                           17      60     89          135        68   93   89                            21      73     136         154   180  84   139  128                           25      90     100                    89   102  97                            28      88     180         172        67   128  127                           33      70     89          174        77   94   101                           40      74     121         159        106  99   112                           47                         202        86   99   129                           49      88     90          201                  126                           54      89     60          120        91        90                            61      74     102         128        98        101                           69      83     114         156        77        108                           ______________________________________                                    

                  TABLE 10                                                        ______________________________________                                        Glucose (mg/dl) (Normal 70-150)                                                      Patient                                                                       8    9      10      2,7  2,8   2,9  Ave                                       Dose (mg/Kg)                                                           Study Day                                                                              40     40     40    40   40    40   40                               ______________________________________                                        0        94     118    100   115  222   98   125                              1        114    114          95   116   87   105                              7        96     78     156   153        117  119                              9        115    130    84    123  148   148  125                              14       87     151    123   102  184   126  129                              17       91     145    93    117  251   139  139                              21       103    156    106   104        90   112                              25       96     210    143   122  278   114  161                              28       125    151    91    154        87   122                              33       122    109               244   121  149                              40       67     128    94         139   92   104                              47       116    75     100              105  99                               49       122                      129   132  128                              54       136    145    79         185   105  132                              61       102    121    92               104  105                              69       135    89     74         205   92   119                              ______________________________________                                    

Equivalents

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed is:
 1. A method of treating or preventing a glucosemetabolic disorder in a subject afflicted with said disorder, comprisingadministering to said subject an amount of a creatine compound, or apharmaceutically acceptable salt thereof, effective to regulate saidsubject's glucose level, such that treatment occurs.
 2. The method ofclaim 1 wherein said disorder is hyperglycemia.
 3. The method of claim 1wherein said disorder is insulin dependent diabetes mellitus.
 4. Themethod of claim 1 wherein said disorder is impaired glucose tolerance.5. The method of claim 1 wherein said disorder is hyperinsulinemia. 6.The method of claim 1 wherein said disorder is insulin insensitivity. 7.The method of claim 1 wherein said disorder is diabetes relateddiseases.
 8. The method of claim 1 wherein the subject is a mammal. 9.The method of claim 8 wherein the subject is a human.
 10. A method fortreating a metabolic disorder selected from the group consisting ofhyperglycemia, insulin dependent diabetes mellitus, impaired glucosetolerance, hyperinsulinemia, insulin insensitivity, diabetes relateddiseases, in a subject afflicted with said disorder, comprisingadministering to the subject a therapeutic amount of a creatine analoguehaving the general formula: ##STR34## and pharmaceutically acceptablesalts thereof, wherein: a) Y is selected from the group consisting of:--CO₂ H--NHOH, --NO₂, --SO₃ H, --C(═O)NHSO₂ J and --P(═O)(OH)(OJ),wherein J is selected from the group consisting of: hydrogen, C₁ -C₆straight chain alkyl, C₃ -C₆ branched alkyl, C₂ -C₆ alkenyl, C₃ -C₆branched alkenyl, and aryl;b) A is selected from the group consistingof: C, CH, C₁ -C₅ alkyl, C₂ -C₅ alkenyl, C₂ -C₅ alkynyl, and C₁ -C₅alkoyl chain, each having 0-2 substituents which are selectedindependently from the group consisting of:1) K, where K is selectedfrom the group consisting of: C₁ -C₆ straight alkyl, C₂ -C₆ straightalkenyl, C₁ -C₆ straight alkoyl, C₃ -C₆ branched alkyl, C₃ -C₆ branchedalkenyl, and C₄ -C₆ branched alkoyl, K having 0-2 substituentsindependently selected from the group consisting of: rromo, chloro,epoxy and acetoxy; 2) an aryl group selected from the group consistingof: a 1-2 ring carbocycle and a 1-2 ring heterocycle, wherein the arylgroup contains 0-2 substituents independently selected from the groupconsisting of: --CH₂ L and --COCH₂ L where L is independently selectedfrom the group consisting of: bromo, chloro, epoxy and acetoxy; and 3)--NH--M, wherein M is selected from the group consisting of: hydrogen,C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₁ -C₄ alkoyl, C₃ -C₄ branched alkyl, C₃-C₄ branched alkenyl, and C₄ branched alkoyl; c) X is selected from thegroup consisting of NR₁, CHR₁, CR₁, O and S, wherein R₁ is selected fromthe group consisting of:1) hydrogen; 2) K where K is selected from thegroup consisting of: C₁ -C₆ straight alkyl. C₂ -C₆ straight alkenyl, C₁-C₆ straight alkoyl, C₃ -C₆ branched alkyl, C₃ -C₆ branched alkenyl, andC₄ -C₆ branched alkoyl, K having 0-2 substituents independently selectedfrom the group consisting of: bromo, chloro, epoxy and acetoxy; 3) anaryl group selected from the group consisting of a 1-2 ring carbocycleand a 1-2 ring heterocycle, wherein the aryl group contains 0-2substituents independently selected from the group consisting of: --CH₂L and --COCH₂ L where L is independently selected from the groupconsisting of: bromo, chloro, epoxy and acetoxy; 4) a C₅ -C₉a-amino-w-methyl-w-adenosylcarboxylic acid attached via the w-methylcarbon; 5) 2 C₅ -C₉ a-amino-w-aza-w-methyl-w-adenosylcarboxylic acidattached via the w-methyl carbon; and 6) a C₅ -C₉a-amino-w-thia-w-methyl-w-adenosylcarboxylic acid attached via thew-methyl carbon; d) Z₁ and Z₂ are chosen independently from the groupconsisting of: ═O, --NHR₂, --CH₂ R₂, --NR₂ OH; wherein Z₁ and Z₂ may notboth be ═O and wherein R₂ is selected from the group consisting of:1)hydrogen; 2) K, where K is selected from the group consisting of: C₁ -C₆straight alkyl; C₂ -C₆ straight alkenyl, C₁ -C₆ straight alkoyl, C₃ -C₆branched alkyl, C₃ -C₆ branched alkenyl, and C₄ -C₆ branched alkoyl, Khaving 0-2 substituents independently selected from the group consistingof: bromo, chloro, epoxy and acetoxy; 3) an aryl group selected from thegroup consisting of a 1-2 ring carbocycle and a 1-2 ring heterocycle,wherein the aryl group contains 0-2 substituents independently selectedfrom the group consisting of: --CH₂ L and --COCH₂ L where L isindependently selected from the group consisting of: bromo, chloro,epoxy and acetoxy; 4) 2 C₄ -C₈ a-amino-carboxylic acid attached via thew-carbon; 5) B, wherein B is selected from the group consisting of:--CO₂ H--NHOH, --SO₃ H, --NO₂, OP(═O)(OH)(OJ) and --P(═O)(OH)(OJ),wherein J is selected from the group consisting of: hydrogen, C₁ -C₆straight alkyl, C₃ -C₆ branched alkyl, C₂ -C₆ alkenyl, C₃ -C₆ branchedalkenyl, and aryl, wherein B is optionally connected to the nitrogen viaa linker selected from the group consisting of: C₁ -C₂ alkyl, C₂alkenyl, and C₁ -C₂ alkoyl; 6) --D--E, wherein D is selected from thegroup consisting of: C₁ -C₃ straight alkyl, C₃ branched alkyl, C₂ -C₃straight alkenyl, C₃ branched alkenyl, C₁ -C₃ straight alkoyl, aryl andaroyl; and E is selected from the group consisting of: --(PO₃)_(n) NMP,where n is 0-2 and NMP is ribonucleotide monophosphate connected via the5'-phosphate, 3'-phosphate or the aromatic ring of the base;--[P(═O)(OCH₃)(O)]_(m) --Q, where m is 0-3 and Q is a ribonucleosideconnected via the ribose or the aromatic ring of the base;--[P(═O)(OH)(CH₂)]_(m) --Q, where m is 0-3 and Q is a ribonucleosideconnected via the ribose or the aromatic ring of the base; and an arylgroup containing 0-3 substituents chosen independently from the groupconsisting of: Cl, Br, epoxy, acetoxy, --OG, --C(═O)G, and --CO₂ G,where G is independently selected from the group consisting of: C₁ -C₆straight alkyl, C₂ -C₆ straight alkenyl, C₁ -C₆ straight alkoyl, C₃ -C₆branched alkyl, C₃ -C₆ branched alkenyl, C₄ -C₆ branched alkoyl, whereinE may be attached to any point to D, and if D is alkyl or alkenyl, D maybe connected at either or both ends by an amide linkage; and 7) --E,wherein E is selected from the group consisting of --(PO₃)_(n) NMP,where n is 0-2 and NMP is a ribonucleotide monophosphate connected viathe 5'-phosphate, 3'-phosphate or the aromatic ring of the base;--[P(═O)(OCH₃)(O)]_(m) --Q, where m is 0-3 and Q is a ribonucleosideconnected via the ribose or the aromatic ring of the base;--[P(═O)(OH)(CH₂)]_(m) --Q, where m is 0-3 and Q is a ribonucleosideconnected via the ribose or the aromatic ring of the base; and an arylgroup containing 0-3 substituents chose independently from the groupconsisting of: Cl, Br, epoxy, acetoxy, --OG, --C(═O)G, and --CO₂ G,where G is independently selected from the group consisting of: C₁ -C₆straight alkyl, C₂ -C₆ straight alkenyl, C₁ -C₆ straight alkoyl, C₃ -C₆branched alkyl, C₃ -C₆ branched alkenyl, C₄ -C₆ branched alkoyl; and ifE is aryl, E may be connected by an amide linkage; e) if R₁ and at leastone R₂ group are present, R₁ may be connected by a single or double bondto an R₂ group to form a cycle of 5 to 7 members; f) if two R₂ groupsare present, they may be connected by a single or a double bond to forma cycle of 4 to 7 members; and g) if R₁ is present and Z₁ or Z₂ isselected from the group consisting of --NHR₁, --CH₂ R₂ and --NR₂ OH,then R₁ may be connected by a single or double bond to the carbon ornitrogen of either Z₁ or Z₂ to form a cycle of 4 to 7 members.
 11. Themethod of claim 10 wherein the creatine compound is administered incombination with insulin or a sulphonylurea compound.
 12. The method ofclaim 10 wherein the creatine compound is cyclocreatine.
 13. The methodof claim 10 wherein the creatine compound is creatine phosphate.
 14. Amethod for treating a metabolic disorder selected from the groupconsisting of hyperglycemia, insulin dependent diabetes mellitus,impaired glucose tolerance, hyperinsulinemia, insulin insensitivity,diabetes related diseases, in a subject afflicted with said disordercomprising administering to the subject an effective therapeutic amountof a substrate of creatine kinase, wherein said effective therapeuticamount is effective to regulate said subject's glucose level, such thattreatment occurs.
 15. A method for treating a glucose metabolic disorderselected from the group consisting of hyperglycemia, insulin dependentdiabetes mellitus, impaired glucose tolerance, hyperinsulinemia, insulininsensitivity, diabetes related diseases in a subject afflicted withsaid disorder comprising administering to the subject an effectivetherapeutic amount of a creatine phosphate analogue.